Uric acid is the final oxidation product of purine metabolism and is mainly excreted in urine. It has been reported to have an antioxidative activity and also a function of protecting neuronal cell [Ames, B. N. et al. Proc. Natl. Acad. Sci. USA, 78, 6858-6862 (1981); Becker, B. F., et al., Free Racical Biol. Med. 14, p 615-631 (1993); Keller, J. N. et al., J. Neurosci. p 687-697 (1998)].
Purine sources, generated from nucleotides existing in cells constituting a living body, and excessively purine-free diet converge at the common intermediate xanthine by in vivo biosynthesis procedure, and uric acid is finally produced by enzymatic reaction with xanthine oxidase, the key enzyme in taking the purines all of the way to uric acid, in liver [F. Borges et al. Current Medi. Chem., 9, p 195-217 (2002)]. The level of daily uric acid produced in body is approximately 700 mg. Of this total, 60˜70% (˜500 mg/day) is excreted through kidney and the residual amount (˜200 mg/day) is excreted through intestine [Japan Clinic History, Japan Clinic Hyperuricemia Hypouricemia, p 161, 166 (2003)].
Hyperuricemia is the abnormally high level of uric acid in blood. In human, it is defined the condition that serum uric acid concentration is higher than normal (7-8 mg/dl for male, 6 mg/dl for female). It is associated with underexcretion of uric acid in the kidney or overproduction of uric acid in the liver. Gouty patient has a remarkably higher level uric acid in blood than normal (7˜8 mg/dl for male, 6 mg/dl for female). Gout is often associated with hyperuricemia. Gout is a type of inflammatory arthritis that is triggered by the crystallization of uric acid within the joint—mostly peripheral ones like the toes and fingers. Acute gout is typically intermittent, constituting one of the most painful experienced by human. Chronic gout usually develops after years of acute intermittent gout. Needle-like monosodium urate (MSU) crystals can be deposited on connective soft tissues such as the articular cartilage in the joint, tendon and ligament. These crystals prick muscles or chondrocyte around the joint and then lead to inflammatory arthritis, which causes swelling, redness, heat, pain, and stiffness in the joints. Urate crystals are directly able to initiate, to amplify, and to sustain an intense inflammatory attack because of their ability to stimulate the release of inflammatory mediators. The urate crystals are deposited mainly in metatarsophalangeal joint of big toe, and rarely in lumbar spine [Vervaeck M., et al., Clinical Neurology and Neurosurgery, 93, p 233-236 (1991)].
Gout is a very dangerous factor because it may cause a complication of various metabolic diseases such as diabetes, hypertension, heart disease, obesity, nephrolithiasis, urolithiasis or the like. Peak incidence of gout is observed predominantly male in age of 40 to 50's and female patients increase in postmenopausal period. Also, the onset frequency is high in obese persons and those exercising extremely.
Incidence of gouty attack is closely associated with patients who have had hyperuricemia for years. It has been reported that incidence of gouty attack is 4.9% when uric acid level in body is 9 mg/dl or higher, 0.5% when uric acid level in body is 7.0˜8.9 mg/dl and 0.1% when uric acid level in body is 7.0 mg/dl or lower, and accumulated incidence of gouty attack for 5 years is about 22% in patients having uric acid level in body of 9 mg/dl or higher [Campion E. W. et al., Am. J. Med., 82, p 421-426 (1987)].
As mentioned above, the amount of urate in the body depends on the balance between dietary intake, synthesis, and the excretion rate. For patients having an high level of uric acid in blood, pathogenesis of hyperuricemia and gout result from urate underexcretion (90%), overproduction (10%) or often a combination of the two [Choi et al., Ann. Intern. Med. p 499-516 (2005)]. Considering such causes of hyperuricemia and gout, development of uricosuric agent is more effective in hyperuricemia/gout management than those suppressing uric acid production. Urate level in human plasma is higher than those of most other mammals. Human are the only mammals in whom gout is known to develop spontaneously. This is because during evolutionary process, human and primate have lost the gene for uricase in liver which is known as enzyme for degradation of uric acid (Uricase enzyme; catalyzing the conversion of uric acid to more soluble compound allantoin) [Fields, M. et al., Free Radical Biol. Med., 20, p 595 (1996); Haliwell, B. Uric acid: an example of antioxidant evaluation, E. Cadenas and L. Packer Editors, Handbook of Antioxidants, Marcel Dekker New York (1996)] and have had a reuptake system of uric acid in kidney by which most of filtered urate from glomerulus is reabsorbed through renal tubule.
A recent literature has reported a gene (SLC22A12) encoding human urate anion transporter 1 (hURAT1), an anion exchange membrane transporter specifically responsible for the function of reabsorption of filtered urate in kidney. The transporter (hURAT1) belongs to organic anion transporter family (OATs) and it has been reported that human urate anion transporters exist in proximal renal tubule through immunochemical experiments and is an important role in urate reuptake through urate absorption experiments by using brush border membrane vesicle (BBMV) of human kidney. Therefore, the human urate anion transporter 1 (hURAT1) has been proved as a useful target molecule for developing treatment agents of diseases associated with uric acid such as hyperuricemia and gout [Enomoto A. et al., Nature, 417, p 447-452 (2002)].
In physicochemical properties, uric acid has the acidity (pKa) of 5.75 and exists in acid form (uric acid) or anionic form (urate) depending on pH. Thus, the protein structure of human urate anion transporter 1 (hURAT1) having a functional similarity is expected to have similar structural characteristics with proteins belonging to organic anion transporter family (OATs). Actually, it has been reported that the amino acid sequence of OAT4 (SLC22A12) among organic anion transporter family (OATs) transporting anion present in apical membrane of proximal tubule has a homology of 42% with that of human urate anion transporter 1 (hURAT1) protein [Enomoto A. et al., Nature, 417, p 447-452 (2002)].
Up to the present, six (6) of transporters in living body have been identified (OAT1 to 4 and URAT1, and OATS of rodents) which are involved in absorption and excretion of anionic substances in kidney that are made from various endogenous substances, xenobiotics and drugs. Their main target substrates are various and different from each other. Meanwhile, as a main substrate for human urate anion transporter 1 (hURAT1), only the uric acid is known [Nahohiko Anzai, et al., J phamacol. Sci., 100, p 411-426 (2006)].
As treatment or prophylaxis agents for hyperuricemia and gout, benzbromarone that is an uricosuric agent having the inhibitory activity of hURAT1-mediated urate reabsorption, as well as probenecid and sulfinpyrazone is currently used. However, these drugs do not have sufficient activities to URAT1. In particular, benzbromarone has some demerits in view of adverse effects. Benzbromarone shows a strong inhibitory function to 2C9 protein among cytochrome P450 (CYP450) proteins and thus has a possibility of drug-drug interaction. Formation of reactive metabolite also has been reported from glutathione (GSH) conjugate formation experiments [Dermot F. McGinnity et al., Drug Metabolism and Disposition, 33, p 1700-1707 (2005)]. Furthermore, because benzbromarone has a benzofuran backbone similar with drug structures of benziodarone, benzarone and amiodarone which are drugs reported to show hepatotoxicity, it has a problem of death due to hepatotoxicity induction as well as adverse effect of liver injury. Therefore, a liver function of patients who intend to take this drug must be examined before the administration, and even during the administration, it is recommended in therapy to check out for a certain period (six months) on whether the hepatotoxicity is induced or not. For these reason, there still remains an unmet medical need for the treatment of diseases associated with uric acid such as hyperuricemia and gout [Hautekeete M. L., et al., Liver, 15, p 25-29 (1995); Makoto Arai, et al., Journal of Gastroenterology and Hepatology 17, p 625-626 (2002); Saitama medical college magazine, 30, 187-194 (2003); Priska Kaufmann, et al., HEPATOLOGY, 41, p 925-935 (2005)].
Pharmacokinetic data of benzbromarone are as follows: As for the concentration in blood, when 2 tablets (50 mg/tablet) are administered one time to a healthy and fasting adult, time of maximum drug concentration in blood (Tmax) of unmodified benzbromarone is 2.7±1.0 hr, half-life of drug is 5.4±1.9 hr, area under the curve (AUC) is 15.9±3.3 μg·h/ml, and maximum concentration of drug (Cmax) is 2.3±0.8 μg/ml. In case of 6-hydroxy benzbromarone which is a metabolite of benzbromarone, time of maximum drug concentration in blood (Tmax) is 4.8±1.3 hr, half-life of drug is 18.0±2.9 hr, area under the curve (AUC) is 39.9±4.4 h/ml, and maximum concentration of drug (Cmax) is 1.7±0.4 μg/ml. As for the part and amount of drug excretion, the excretion rate of 6-hydroxy benzbromarone in urine was 1.2% of the administered amount until 72 hours after administration. However, the benzbromarone was not detected in urine at all [Urinome international interview (2005); Oikawa Tosihiro et al., New drug and Clinic, 53, p 682 (2004)].
Recently, one patent was disclosed and registered in Japan for compounds which inhibit human urate anion transporter 1 (hURAT1) as an uricosuric agent and have a weak inhibitory effect on cytochrome P450 2C9 (CYP2C9) [Japan Tobacco, WO2006/057460 and JP3988832 B2].